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Coming dissertations at MedFak

  • Molecular studies of endocrine tumors : Insights from genetics and epigenetics Author: Samuel Backman Link: Publication date: 2020-11-19 10:25

    Endocrine tumors may be benign or malignant and may occur in any of the hormone producing tissues. They share several biological characteristics, including a low mutation-burden, and may co-occur in several hereditary tumor syndromes. The aim of this thesis was to identify genetic and epigenetic aberrations in endocrine tumors.

    In paper I we performed a comprehensive DNA methylation analysis of 39 pheochromocytomas/paragangliomas as well as 4 normal adrenal medullae on the HumanMethylation27 BeadChip array. We validated two previously described clusters based on DNA methylation with distinct genetic associations.

    In Paper II we performed a transcriptomic analysis of 15 aldosterone producing adenomas. CTNNB1-mutated tumors were found to form a distinct subgroup based on gene expression and to share gene expression similarities with non-aldosterone producing adrenocortical tumors with CTNNB1 mutations, including overexpression of AFF3 and ISM1.

    In paper III we used whole genome sequencing to identify germline genetic variants in 14 patients with Multiple Endocrine Neoplasia type 1 previously found to be wildtype for the MEN1 gene on routine clinical testing. Three patients were found to carry previously undetected MEN1 mutations. Two patients were confirmed to have phenocopies caused by variants affecting CASR or CDC73. In total 9/14 patients were not found to have a disease-causing germline variant, suggesting that the syndrome may in some cases be due to chance co-occurrence of several sporadic tumors.

    In paper IV RNA-Seq and whole genome sequencing of a cohort of SI-NETs selected on the basis of unusually short or long survival was performed in order to identify disease causing genes and potential prognostic factors. We confirmed known genetic aberrations and found rare variants in known cancer driver genes. Based on gene expression two clusters that differ in prognosis were detected. Moreover, through integration of copy number variation data and gene expression, we identied novel potential disease causing genes.

  • Insights into the Effects of Type 2 Diabetes on Bone Health Author: Adam Mitchell Link: Publication date: 2020-11-19 09:22

    Individuals with type 2 diabetes mellitus (T2DM) have an increased risk of hip fracture, despite a stable or even greater bone mineral density (BMD). Bone area is linked to hip fracture risk independent of BMD and smaller bone area has been reported in T2DM subjects at the radius and tibia, but information at the hip is lacking. The Mediterranean diet is associated with a lower risk of hip fracture yet the mechanisms are unclear. The diet’s effect on T2DM status may be a possible mechanism. This thesis aims to discern the effects fasting glucose levels and T2DM have on bone.

    In paper I, clinical cut offs of fasting glucose used to define T2DM, were used to explore the association with BMD, bone area and bone turnover markers in the Swedish mammography cohort clinical (SMCC) and the Uppsala longitudinal study of adult men (ULSAM). T2DM was associated with greater BMD yet lower bone area at the total hip when compared to those without T2DM. T2DM was also associated with lower levels of bone turnover markers.

    In paper II, a Mendelian randomisation (MR) study was used to assess the potential causal effects of genetically predicted fasting glucose concentrations on bone area and BMD in partici-pants from SMCC, the prospective investigation in the vasculature of Uppsala seniors (PIVUS) and ULSAM. Results suggest an increase in genetically predicted fasting glucose concentrations may be a causal risk factor for lower bone area and possibly greater BMD.

    In paper III, the association between T2DM status and change in bone area and BMD over 8 years, was analysed in the SMCC, PIVUS and ULSAM. Those with incident T2DM had a lesser expansion in bone area at the total hip compared to those without T2DM.

    In paper IV, causal inference mediation analyses were used to estimate the direct effect of Mediterranean diet on the risk of hip fracture and the possible mediating effects of T2DM and BMI in the Swedish mammography cohort (SMC) and the cohort of Swedish men (COSM). Results showed a direct effect of the Mediterranean diet on the risk of hip fracture but ruled out the effects of T2DM and BMI as major mediators.

    In summary, T2DM and fasting glucose were associated with lower bone area at the hip. This may provide important mechanistic evidence as to why those with T2DM have a greater risk of hip fracture. We cannot rule out mediation or counteracting effects but there is an effect of Medi-terranean diet on hip fracture that does not go through T2DM and BMI.

  • Targeting toddlers’ communication difficulties at the Swedish child health services – a public health perspective Author: Anna Fäldt Link: Publication date: 2020-11-18 13:54

    Communication is fundamental for human interaction. Communication difficulties have a negative impact on children’s learning, relations, and quality of life and are regarded as a public health problem. The Swedish child health services have a possibility to prevent communication difficulties and their consequences for the individual through universal interventions and identification of affected children. This thesis investigates interventions at the levels of universal prevention, identification, and indicated intervention for children with communication difficulties.

    Study I explored associations between family and child health centre characteristics and exposure to a universal preventive communication intervention. Questionnaires answered by 2326 mothers and 2077 fathers were analysed. Few parents reported that they had been exposed to the intervention. Positive associations were seen to high socioeconomic status and if the child was of low age at the start of the intervention or was oldest among siblings. Study II described the study design employed to investigate the identification and effects of an indicated intervention. Study III used a mixed-methods design to explore child health service nurses’ experiences and sense of competence when using the Infant-Toddler Checklist (ITC) at the 18-month health visit. The nurses considered the ITC to be a beneficial tool both in communicating with families and in identifying children with communication difficulties. The ITC seemed to enhance nurses’ and parents’ awareness of the child’s communication.

    In study IV, the psychometric properties of the ITC were analysed using data on 679 children. A sensitivity of 86% and specificity of 59% were found. These measures improved when combining the ITC with the child health service nurses’ informal developmental surveillance. Study V explored parents’ perceptions of the intervention ComAlong Toddler, consisting of five group sessions and two individual home visits. The parental intervention focused on responsive communication, enhanced milieu teaching and augmentative and alternative communication. Qualitative content analysis showed that parents appreciated the intervention and used the strategies taught. Parents described benefits of the combination of home visits and group sessions with peer learning through video recorded home assignments.

    In conclusion, the thesis shows that the ITC can be implemented in the child health services as the method identifies children with communication difficulties and seems to have preventive capabilities. ComAlong Toddler may help parents to implement communication-enhancing strategies with their children. When universal interventions are delivered through the child health services, implementation and distribution need to be carefully planned and carried out so that they reach all children.